Dr. Phillips is an internist and Associate Professor of Clinical Medicine at Morehouse School of Medicine, Atlanta, GA. The candidate's long-term goal is to develop an independent career with expertise in the application of genetic epidemiology, translational research methods and health services research to improve primary prevention, risk stratification and management of cardiovascular disease among racial and ethnic minorities. Dr. Phillips'is committed to developing a research career in primary prevention of cardiovascular disease and health disparities. His previous research has been focused on improving quality of care and clinical outcomes with respect to heart failure disease management programs and health disparities. However, during the recent two years the applicant has expanded his research focus to more upstream targets for secondary prevention of cardiovascular disease including hypertension which is a common, important modifiable risk factor and an antecedent to cardio-renal dysfunction, particularly in African Americans. Therefore, this career development and clinical research training program will enable the applicant to acquire additional training in genetic epidemiology and translational research including clinical applications of gene- expression, proteomics and biomarker profiling to improve risk stratification and predict disease progression and/or response to therapy. First, the proposed career development plan incorporates a multi-disciplinary training program designed to provide an intense, closely mentored, patient-oriented research experience. Second, the candidate will also enroll in a structured curriculum of didactic coursework in genetic epidemiology, advanced biostatics and longitudinal data management, translational research, clinical trial design and research ethics. Third, the training environment and mentoring team are well aligned to provide both the necessary resources and considerable expertise in genetic epidemiology and translational research, hypertension and vascular dysfunction. The primary mentor is Dr. Gary H. Gibbons who is Director of the Cardiovascular Research Institute (CVRI) at Morehouse School of Medicine and a Co-mentor Dr. Arlene B. Chapman, Director of the Atlanta Clinical and Translational Science Institute (ACTSI) who have established track records of success and experience with mentoring junior faculty and post-doctoral trainees towards independent research careers. Finally, the candidate will also design, implement and complete a clinical research project in order to develop pilot data which will be important for the success of future funding applications on the path to independence. The candidate is interested in the natural history of treatment resistant hypertension (defined as BP>140/90 mmHg despite >3 antihypertensive agents at optimum dose including a diuretic) in African Americans. Hypertension experts suggest prevalence estimates in the range of 8% to 30%. However, epidemiologic studies pertaining to this important public health problem are sparse in African Americans. During the award period, the candidate will design and implement a pilot study of African American subjects (N=247 cases versus N=247 controls with BP <140/90mmHg and <2 drugs) to test a series of interrelated hypotheses: i) African Americans with treatment resistant hypertension have higher levels of pro-inflammatory cytokines), biomarkers of acute and chronic renal injury (microalbuminuria, proteinuria and kidney injury marker-1 [KIM-1]), and increased vascular stiffness (pulse wave velocity [PWV] and augmentation index [Aix]) compared with age/sex matched controls: ii) Allele frequencies for gain of function angiotensinogen (AGT) variants and AGT levels are significantly higher: iii) levels of pro-inflammatory cytokines, biomarker of renal injury, AGT variants modify systemic and intra-renal RAAS activation have additive effects on predicting renal dysfunction during follow-up. PUBLIC HEALTH RELEVANCE: This is a pilot study of African American subjects with treatment resistant hypertension (BP >140/90mmHg despite >3 antihypertensive agents at optimum dose including a diuretic versus controls with BP <140/90mmHg and <2 drugs including a diuretic) to test a series of interrelated hypotheses: i) African Americans with treatment resistant hypertension have higher levels of pro-inflammatory cytokines), biomarkers of acute and chronic renal injury (microalbuminuria, proteinuria and kidney injury marker-1 [KIM-1]), and increased vascular stiffness (pulse wave velocity [PWV] and augmentation index [Aix]) compared with age/sex matched controls: ii) Allele frequencies for gain of function angiotensinogen (AGT) variants and AGT levels are significantly higher: iii) levels of pro-inflammatory cytokines, biomarker of renal injury, AGT variants modify systemic and intra-renal RAAS activation and have additive effects on predicting renal dysfunction (incident CKD diagnosis defined as GFR <60ml/min or doubling of serum creatinine) during follow-up.